Cancers, or malignant neoplasms, include a large group of different diseases, all of which involve at least in part unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors. The malignant tissue may invade nearby tissues, or spread to more distant parts of the body through the lymphatic system or bloodstream. Cell division is a complex process that is normally tightly regulated, and generally, healthy cells control their own growth and will destroy themselves if growth becomes sufficiently dysregulated. Some cancers occurs when problems in the genes of a cell prevent these controls from functioning properly. These problems may come from damage to the gene or may be inherited, and can be caused by various sources inside or outside of the cell. Faults in two types of genes are especially important: oncogenes, which drive the growth of cancer cells, and tumor suppressor genes, which prevent cancer from developing.
Cancer is usually treated with chemotherapy, radiation therapy and surgery. The chances of surviving the disease vary greatly depending upon the type and location of the cancer and the extent of disease at the start of treatment. While cancer can affect people of all ages, and a few types of cancer are more common in children, the risk of developing cancer generally increases with age. In 2007, cancer caused about 13% of all human deaths worldwide (7.9 million).
Depending upon the tissue or tumor type, cancers may be categorized. For example, carcinomas are generally cancers derived from epithelial cells. This group includes many of the most common cancers, particularly in the aged, and include nearly all those developing in the breast, prostate, lung, pancreas, and colon. Sarcomas are generally cancers arising from connective tissue, such as bone, cartilage, fat, and nerve tissue, each of which develop from cells originating in mesenchymal cells outside the bone marrow. Lymphomas and leukemias include two classes of cancers that arise from hematopoietic (blood-forming) cells that leave the marrow and tend to mature in the lymph nodes and blood, respectively. Germ cell tumors are generally cancers derived from pluripotent cells, most often presenting in the testicle or the ovary. Blastomas are generally cancers derived from immature “precursor” cells or embryonic tissue, and may occur more commonly in children.
Malignant gliomas are highly invasive and neurologically destructive tumors, the most aggressive manifestation of which is glioblastoma. The term glioma encompasses a group of cancers that includes astrocytomas, oligodendrogliomas, oligoastrocytomas, and ependymomas. The most widely used scheme for classification and grading of glioma is that of the World Health Organization, where gliomas are classified according to their hypothesized line of differentiation, such as whether they display features of astrocytic, oligodendrial or ependymal cells. They are graded on a scale of I to IV according to their degree of malignancies. For example, glioblastoma (GBM) is classified as grade IV anaplastic astrocytoma.
Glioblastoma is the most common primary brain tumor in adults. More than half of the 18,000 patients diagnosed with malignant primary brain tumors in US each year have GBM. GBM is an anaplastic, highly cellular tumor, with high proliferation indices, microvascular proliferation and focal necrosis. Signs and symptoms depend on several factors, including size, rate of growth, and localization of the tumor within the brain, and are mainly represented by headache, seizures, neurological deficits, and changes in mental status. GBM prognosis remains pessimistic. Survival time is less than 2 years for the majority of patients. Karnofsky performance status (KPS) is one of the most important prognostic factors. For example, patients with KPS>70 are alive at 18 months in approx 18% of cases, compared with 13% of patients with lower KPS scores. Primary GBM develops de novo from glial cells, typically has a clinical history of less than six months, is more common in older patients and presents small-cell histology. Secondary GBM develops over months or years from pre-existing low-grade astrocytomas, predominantly affects younger people and presents giant-cell histology. Current therapies in both neoadjuvant or adjuvant therapy have been reported to prolong disease-free survival but not overall survival.
Melanoma, is a malignant neoplasm of melanocytes and is reportedly the most deadly form of skin cancer (Chudnovsky et al., 2005). The incidence of melanoma has been reported to continue to increase despite public health initiatives to promote protection against harmful effects of the sun. In Europe, approximately 26,100 males and 33,300 females are diagnosed each year with melanoma, and about 8,300 males and 7,600 females die from the disease. It is the eighth most commonly diagnosed cancer in females and seventeenth in males. Light skin type, large numbers of nevi and excessive sun exposure, mainly in childhood, are reportedly the major modifiers of melanoma risk (Houghon and Polsky, 2002). When melanoma is detected in its early stages it is curable, but once advanced it becomes more difficult to treat. The primary lesions are located in limbs (22%), trunk (40%), head and neck (15%), and 16% in other sites (Capizzi and Donohue, 1994). The most common sites of metastases found in the autopsy are skin and subcutaneous tissue (75%), lung (70%), liver (68%), small intestine (58%), pancreas (53%), heart (49%), brain (39%), and spleen (36%). With visceral metastasis, the 5-year survival drops to approximately 6%, and the median survival from time of diagnosis is 7.5 months (Barth et al, 1995).
Thyroid cancer generally refers to any of five kinds of malignant tumors of the thyroid gland: papillary, follicular, hurthle cell, medullary, and anaplastic. Papillary and follicular, and hurthle cell tumors are the most common. They grow slowly, and may recur, but are generally not fatal in patients under 45 years of age. Medullary tumors have a good prognosis if restricted to the thyroid gland, but a poorer prognosis if metastasis occurs. Anaplastic tumors are fast-growing and have thusfar responded poorly to all therapies.
Thyroid nodules are diagnosed by ultrasound guided fine needle aspiration (USG/FNA) or frequently by thyroidectomy (surgical removal and subsequent histological examination). Because thyroid cancer can take up iodine, radioactive iodine is commonly used to follow and treat thyroid carcinomas, followed by thyroid stimulating hormone (TSH) suppression using thyroxine therapy.
Thyroid cancer is the most common endocrine malignancy, with 33,500 new cases of thyroid cancers estimated to be diagnosed in the U.S. in 2008. Differentiated thyroid carcinoma comprises 90% of all cases. Once thyroid cancer metastasizes to distant sites and is no longer amenable to radioactive iodine therapy or surgery, expected survival declines rapidly. Currently, there is only one FDA-approved therapy for thyroid cancer.
The treatments of cancer, including malignant gliomas, melanoma, and thyroid cancers, represent unmet medical needs.
It has been discovered that oxazolidinone antibiotics, and pharmaceutically acceptable salts thereof, are useful in treating cancer, and in particular useful against malignant glioma, melanoma and thyroid cancer and are expected to be useful in treating patients suffering from or in need of relief from these cancers. The use of oxazolidinones, or pharmaceutically acceptable salts thereof, in treating cancers, including malignant gliomas, melanoma, and thyroid cancer has heretofore been unknown.